Abstract Hydroxyurea (HU) is the only drug approved by the Food and Drug Administration (FDA) for the prevention of vaso-occlusive pain episodes in sickle cell disease (SCD). This proposal supports a randomized, double-blind, placebo-controlled phase II trial of montelukast (a cysteinyl leukotriene receptor 1 antagonist) combined with HU for the prevention of vaso-occlusive pain episodes in adolescents and adults with SCD. Our investigative team has generated abundant clinical and pre-clinical data implicating cysteinyl leukotrienes (CysLTs) in the pathogenesis of vaso-occlusion. In separate cohorts of children and adults with SCD, baseline levels of CysLTs were associated with the rate of hospitalizations for pain. Further, murine models of SCD treated with montelukast showed decreased vascular congestion and lower levels of the inflammatory marker soluble vascular cell adhesion molecule-1 (sVCAM-1) compared to untreated SCD mice. Montelukast is an FDA- approved therapy that is well tolerated and already widely used in individuals with SCD who also have asthma. We have assembled a multi-disciplinary team to test the hypothesis [that montelukast adds efficacy to HU therapy for improving vaso-occlusion when compared to HU alone]. In this proposal, we will compare participants treated with montelukast and HU to those treated with placebo and HU for a total of 8 weeks. The following specific aims will be tested in adolescents and adults with SCD: Aim 1. [To determine whether montelukast versus placebo added to HU will improve markers of vaso-occlusion-associated tissue injury in adolescents and adults with SCD], and Aim 2. [To evaluate physiologic effects of montelukast versus placebo added to HU in adolescents and adults with SCD]; (Subaim 2A) [To determine if montelukast versus placebo added to HU will improve lung function in adolescents and adults with SCD]; (Subaim 2B) [To determine if montelukast versus placebo added to HU will improve forearm microvascular blood flow in adolescents and adults with SCD], respectively. Anticipating a [20%] dropout rate, we will enroll 63 participants and expect that 50 participants will receive montelukast or placebo therapy for 8 weeks. If this study provides preliminary evidence that montelukast when combined with HU has efficacy for the treatment of vaso-occlusion, we will propose a larger multi-center phase III trial.